1. Introduction
The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein, or any publication specifically or implicitly referenced herein, is prior art, or even particularly relevant, to the presently claimed invention.
2. Background
Conventional cancer treatments include radiotherapy, chemotherapy, and surgery. Recently, the clinical outcome of cancer patients has improved dramatically with combination chemotherapy, and today anticancer research is centering on developing targeted and individualized therapies. Even so, current treatments often do not completely rid patients of their cancers and thus significant challenges remain.
Some chemical antitumor agents that are undergoing clinical evaluation produce low response rates in solid tumors. High cytotoxicity also often occurs as a serious side effect of chemotherapy. Additionally, cancer cells can become resistant to various chemotherapeutic agents directed at them, so overcoming this drug-resistance through the provision of new anticancer agents is an important research focus. For this reason development of novel chemotherapeutic agents for treatment of some cancer types that can become refractory and/or show little responsiveness to current chemotherapy (e.g., colon, prostate, ovarian, and renal cancer, non-small cell lung carcinoma, CNS cancers, and melanoma) is urgently needed.
Ribonucleotide reductase (RR), a critical enzyme for the synthesis of deoxyribonucleotides and cell division, is over-expressed in rapidly dividing cancer cells, making it an important target for cancer therapy (Cerqueira, et al., Recent Pat. Anticancer Drug Discov., vol. 2, 11-29 (2007)). The enzyme is composed of a complex of two subunits, named R1 and R2. The R1 subunit contains the active site, including an essential cysteine designed to become a thiyl radical, and allosteric sites, while the R2 subunit contains a diferric-tyrosyl radical cofactor (Shao, et al., Curr. Cancer Drug Targ., vol. 6, 409-431 (2006)).
There are three broad classes of RR inhibitors. The first class includes nucleoside analogues, which bind to the R1 subunit of the enzyme (Cerqueira, et al., above). Many nucleoside analogues that inhibit R1 subunit activity have been approved for human clinical treatment of cancer, and others are being evaluated in clinical trials (Shao, et al., above).
The second RR inhibitor class is mainly made up of short chain peptides that bind at the interface of the R1 and R2 subunits, thereby interfering with the enzyme activity (Yvan, et al., EP 0383190 (Bio-mega, Inc.), 1990). The third class of RR inhibitors binds with high affinity to the nonheme iron in the R2 subunit (Fox, R. M., in Inhibitors of Ribonucleotide Reductase Activity; Cory, J. G., Cory, A. H., Eds.; Pergamon Press: Oxford, 1989; pp 113-125).
RR inhibitors such as hydroxyurea, didox (3,4-dihydroxybenzohydroxamic acid), trimidox (3,4,5-trihydroxybenzamidoxime), and nitric oxide target the small R2 subunit by directly quenching the tyrosyl radical and/or affecting the iron center (Shao, et al., above). Other R2 inhibitors belong to the class of powerful iron chelators that coordinate with iron through an N*—N*—S* [heterocyclic carboxaldehyde thiosemicarbazones (Agrawal, et al., Prog. Med. Chem., vol. 15, 321-356 (1978)), such as Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) (Finch, et al., Adv. Enzyme Regul., vol. 39, 3-12 (1999); Finch, et al., Biochem. Pharmacol. 59, 983-991 (2000)), and 2,2′-Bipyridyl-6-carbothioamide (BPYTA) (Antonini, et al., J. Med. Chem., vol. 24, 1181-1184 (1981); Nocentini, et al., Cancer Res., vol. 53, 19-26 (1993)). Also, iron chelators that coordinate with iron through an N*—N*—N* tridentate ligand system, such as N-heteroarylhydrazones, are potent R2 inhibitors (Cory, et al., Anticancer Res., vol. 14, 875-880 (1994); Easmon, et al., J. Med. Chem., vol. 40, 4420-4425 (1997); Easmon, et al., J. Med. Chem., vol. 49, 6343-6350 (2006)). Several azinyl hydrazones containing a N*—N*—N* structural motif have also be reported to inhibit tumor cell growth by cytotoxic mechanisms other than RR inhibition (Whitnall, et al., PNAS, vol. 103, 14901-14906 (2006); Richardson, et al., J. Med. Chem. 49, 6510-6521 (2006); Yu, et al., J. Med. Chem. 52, 5271-5294 (2009); Horiuchi, et al., Bioorg. Med. Chem. Lett., vol. 19, 305-308 (2009).
It has also been reported that an N6-substituted adenosine (6-hydrazinopurine-riboside, compound 1, below) and 3′-C-methyl-adenosine (3′-Me-Ado) derivatives are effective cytotoxic agents against various human tumor cell lines (HeLa, HT-29, K562, and MCF-7) (Cappellacci, et al., Eur. J. Med. Chem., vol. 46, 1499-1504 (2011); Cappellacci, et al., J. Med. Chem., vol. 51, 4260-4269 (2008)).
6-Hydrazinopurine-riboside has recently been reported to be a potent mutagenic agent (Graci, et al., Antimicrob. Agents Chemother., vol. 52, 971-979 (2008)), and as inhibiting human RR, possibly by scavenging tyrosyl free radicals involved in the reduction of nucleoside diphosphates.
3′-C-Methyl-adenosine is a purine ribonucleoside that acts as a mechanism-based inhibitor of R1 subunit of mammalian RR, and reportedly has significant antitumor activity against a panel of human leukemia and carcinoma cell lines (Franchetti, et al., J. Med. Chem., vol. 48, 4983-4989 (2005); Cappellacci, et al., J. Med. Chem., vol. 51, 4260-4269 (2008)).
3. Definitions
Before describing the instant invention in detail, several terms used in the context of the present invention will be defined. In addition to these terms, others are defined elsewhere in the specification, as necessary. Unless otherwise expressly defined herein, terms of art used in this specification will have their art-recognized meanings.
An “agent” refers to an active ingredient delivered to achieve an intended therapeutic benefit.
The term “combination therapy” refers to a therapeutic regimen that involves the provision of at least two distinct therapies to achieve an indicated therapeutic effect. For example, a combination therapy may involve the administration of two or more chemically distinct active ingredients, or agents, for example, a hydrazone derivative according to the invention and another chemotherapeutic agent. Alternatively, a combination therapy may involve the administration of one or more hydrazone derivatives, alone or in conjunction with another agent as well as the delivery of another therapy. In the context of the administration of two or more chemically distinct agents, it is understood that the active ingredients may be administered as part of the same composition or as different compositions. When administered as separate compositions, the compositions comprising the different active ingredients may be administered at the same or different times, by the same or different routes, using the same or different dosing regimens, all as the particular context requires and as determined by the attending physician. Similarly, when one or more agents are combined with other drugs, the drug(s) may be delivered before, during, and/or after the period the subject is in therapy.
In the context of this invention, a “liquid composition” refers to one that, in its filled and finished form as provided from a manufacturer to an end user (e.g., a doctor or nurse), is a liquid or solution, as opposed to a solid. Here, “solid” refers to compositions that are not liquids or solutions. For example, such solids include dried compositions prepared by lyophilization, freeze-drying, precipitation, and similar procedures.
“Monotherapy” refers to a treatment regimen based on the delivery of one therapeutically effective compound, whether administered as a single dose or several doses over time.
A “patentable” composition, process, machine, or article of manufacture according to the invention means that the subject matter satisfies all statutory requirements for patentability at the time the analysis is performed. For example, with regard to novelty, non-obviousness, or the like, if later investigation reveals that one or more claims encompass one or more embodiments that would negate novelty, non-obviousness, etc., the claim(s), being limited by definition to “patentable” embodiments, specifically exclude the unpatentable embodiment(s). Also, the claims appended hereto are to be interpreted both to provide the broadest reasonable scope, as well as to preserve their validity. Furthermore, if one or more of the statutory requirements for patentability are amended or if the standards change for assessing whether a particular statutory requirement for patentability is satisfied from the time this application is filed or issues as a patent to a time the validity of one or more of the appended claims is questioned, the claims are to be interpreted in a way that (1) preserves their validity and (2) provides the broadest reasonable interpretation under the circumstances.
A “plurality” means more than one.
The term “species” when used in the context of describing a particular drug species, refers to a population of chemically indistinct molecules.
A “subject” or “patient” refers to an animal in need of treatment that can be effected by molecules of the invention. Animals that can be treated in accordance with the invention include vertebrates, with mammals such as bovine, canine, equine, feline, ovine, porcine, and primate (including humans and non-human primates) animals being particularly preferred examples.